Retinal degenerative diseases, such as macular degeneration and retinitis pigmentosa, are among the leading causes of blindness. Current treatment strategies are aimed at restoring light sensitivity, and assume that surviving retinal circuitry remains relatively intact as photoreceptors degenerate. This paradigm is being challenged by recent findings that reveal a massive structural remodeling of the retina during and after photoreceptor death;retinal circuits compensate for the loss of photoreceptor input during a phased process of remodeling. Although such changes could preclude every aspect of retinal repair by forming networks incapable of transmitting visual signals, the synaptic basis for these changes is unknown. To fill in this gap, in Aim 1, we will record resting activity of identified retinal ganglion cells in mouse models of retinal degeneration to determine the synaptic mechanisms responsible for altered retinal output during progression of the disease. In Aim 2, we will drive retinal circuits with presynaptic stimuli to determine the ability of ganglion cells to process synaptically-evoked responses. Since ganglion cells are the output neurons of the retina, their synaptic inputs reflect the functional state of the retinal circuits responsible for visual processing. Identifying these changes could help to reduce the impact of retinal degeneration by providing new targets to repair or prevent retinal dysfunction. PUBLIC HEALTH RELEVANCE: Progressive photoreceptor cell loss, regardless of its underlying cause, is a hallmark of retinal degenerative diseases that lead to blindness. The retinal network is dynamic as surviving cells seek alternative sources of excitation during the loss of sensory input. It is unknown how plastic changes during retinal degenerations would affect the potential for recovery. The proposed project will establish how the loss of photoreceptor-driven activity affects the physiological properties of the downstream retinal network. By identifying disruptive changes in retinal physiology that accompany photoreceptor degeneration, this study will provide novel targets to treat or prevent visual dysfunction during retinal degenerative diseases.